Neural Tube Defects

• Types
• Causes
• Diagnosis
• Treatment
• Complications

Neural tube defects are the most common severe central nervous system anomalies, only second to cardiovascular abnormalities resulting in congenital morbidity and mortality. The nervous system is ectodermal in origin. The central nervous system consists of the brain and spinal cord formed by folding of dorsal part neural plates under the influence of underlying notochord and prechordal mesoderm and closure of anterior (cranial) and posterior (caudal) neuropores by a process called neurulation that begins as early as 3 and 4 weeks of conception. Failure to complete neurulation results in neural tube defects (NTDs). This activity reviews the role of the interprofessional team in the prevention and treatment of NTDs. The neural tube formation during gestational development is a complicated morphogenic process that requires various cell signaling and regulation by a variety of genes.  It starts during the 3rd and 4th weeks of gestation. This process is called primary neurulation, and it begins with an open neural plate, then ends with the neural plate bending in specific, distinct steps.[rx]

Neural tube defects are the most common severe central nervous system anomalies, second only to cardiovascular abnormalities in causing congenital morbidity and mortality. The nervous system is ectodermal in origin. The central nervous system consists of the brain and spinal cord formed by folding of dorsal part neural plates under the influence of underlying notochord and prechordal mesoderm and closure of anterior (cranial) and posterior (caudal) neuropores by a process called neurulation that begins as early as 3 and 4 weeks of conception—failure to complete neurulation results in neural tube defects (NTDs). Neurulation consists of two phases; primary and secondary neurulation. Primary neurulation is defined as folding the dorsal part of the neural tube and lengthening neural plates in the longitudinal axis, and narrowing the cross-section by the phenomenon called convergent extension forming the brain and spinal cord. Primary neurulation is followed by canalization of neural tubes, forming the distal part of the spinal cord by a process called secondary neurulation.[rx]

Fibroblast growth factor (FGF) signaling concordant with suppression of bone morphogenetic protein 4 (BMP4), which is a transforming growth factor, induces neural plate formation. Also, retinoic acid organizes the cranial-caudal axis by regulating the expression of homeobox genes.[rx] Neural tube defects can be present anywhere from the brain to the end of the spinal cord. Open NTDs are due to failure of primary neuralation and associated with hydrocephalus, Chiari II malformation, etc. Neural tissue is exposed to and associated with cerebrospinal fluid (CSF) leakage. Closed NTDs are due to failure of secondary neuralation and are generally confined to the Spinal cord. Neural tissue is not exposed. The closed neural tube defects occur post neurulation and include lipoma with a dorsal defect (lipomyelomeningocele, lipomyelocele), especially when a subcutaneous mass is present.

Types

There are two classes of NTDs: open, which are more common, and closed. Open NTDs occur when the brain and/or spinal cord are exposed at birth through a defect in the skull or vertebrae (spinal column). Open NTDs include anencephaly, encephaloceles, hydranencephaly, iniencephaly, schizencephaly, and the most common form, spina bifida. Closed NTDs occur when the spinal defect is covered by skin. Types of closed NTDs include lipomeningocele, lipomyelomeningocele, and tethered cord.

Anencephaly

Anencephaly (without a brain) is a severe neural tube defect that occurs when the anterior-most end of the neural tube fails to close, usually during the 23rd and 26th days of pregnancy. This results in an absence of a major portion of the brain and skull. Infants born with this condition lack the main part of the forebrain and are usually blind, deaf, and display major craniofacial anomalies. The lack of a functioning cerebrum will prevent the infant from even gaining consciousness. Infants are either stillborn or usually die within a few hours or days after birth. For example, anencephaly in humans can result from mutations in the NUAK2 kinase.

Encephaloceles

Encephaloceles are characterized by protrusions of the brain through the skull that is sac-like and covered with a membrane. They can be a groove down the middle of the upper part of the skull, between the forehead and nose, or the back of the skull. Due to the range in their location, encephaloceles are classified by the location as well as the type of defect it causes. Subtypes include occipital encephalocele, encephalocele of the carnival vault, and nasal encephaloceles (frontoethmoidal encephaloceles and basal encephaloceles), with approximately 80% of all encephaloceles occurring in the occipital area.^[rx] Encephaloceles are often obvious and diagnosed immediately. Sometimes small encephaloceles in the nasal and forehead are undetected. ^[rx] Despite the wide range of its implications, encephaloceles are most likely to be caused by the improper separation of the surface ectoderm and the neuroectoderm after the closure of the neural folds in the fourth week of gastrulation.^[rx]

Hydranencephaly

Hydranencephaly is a condition in which the cerebral hemispheres are missing and instead filled with sacs of cerebrospinal fluid. People are born with hydranencephaly, but most of the time, the symptoms appear at a later stage. Newborns with hydranencephaly can swallow, cry, and sleep and their head is in proportion to their body. However, after a few weeks, the infants develop increased muscle tone and irritability. After a few months, the brain starts to fill with cerebrospinal fluid (hydrocephalus). This has several consequences. Infants start to develop problems with seeing, hearing, growing and learning. The missing parts of the brain and the amount of cerebrospinal fluid can also lead to seizures, spasms, problems with regulating their body temperature, and breathing and digestion problems. Besides problems in the brain, hydranencephaly can also be seen on the outside of the body. Hydrocephalus leads to more cerebrospinal fluid in the brain, which can result in an enlarged head.

The cause of hydranencephaly is not clear. Hydranencephaly is a result of an injury of the nervous system or abnormal development of the nervous system. The neural tube closes in the 6th week of the pregnancy,^[rx] so hydranencephaly develops during these weeks of the pregnancy. The cause of these injuries/development is not clear.

Theories regarding the causes of hydranencephaly include:^[rx]

• blockage in the carotid artery: some researchers think that a blockage of the carotid artery leads to the under-/no development of the brain. The carotid artery is the most important blood supplier of the brain. With a blockage, the brain barely receives blood. Blood is necessary for the development and keeping intact of the brain.^[rx]
• inherited condition.^[rx]
• Infection: during the pregnancy, a woman can develop an infection in the uterus which can lead to problems with the neural tube.^[rx]
• environmental toxins: during the pregnancy, a woman can be exposed to environmental toxins that can affect the health of the infant.^[rx]

Iniencephaly

• Iniencephaly is a rare neural tube defect that results in extreme bending of the head to the spine. The diagnosis can usually be made on antenatal ultrasound scanning, but if not will undoubtedly be made immediately after birth because the head is bent backward and the face looks upwards. Usually, the neck is absent. The skin of the face connects directly to the chest and the scalp connects to the upper back. Individuals with iniencephaly generally die within a few hours after birth.

Myeloschisis

• Exposed neural tissue without skin or meninges covering. Myeloschisis is a flat neural tube defect without a layer of skin covering the opening in the spine. With myeloschisis, the spinal cord and the surrounding nerve tissue are also exposed to the amniotic fluid. This form of spina bifida has similar risks and symptoms as myelomeningocele.

Spina bifida

Spina bifida is further divided into two subclasses, spina bifida cystica and spina bifida occulta.

• Spina bifida cystica includes meningocele and myelomeningocele. Meningocele is less severe and is characterized by herniation of the meninges, but not the spinal cord, through the opening in the spinal canal. Myelomeningocele involves herniation of the meninges as well as the spinal cord through the opening.^[rx]
• Spina bifida occulta means hidden split spine.^[rx] In this type of neural tube defect, the meninges do not herniate through the opening in the spinal canal.^[rx] The most frequently seen form of spina bifida occulta is when parts of the bones of the spine, called the spinous process, and the neural arch appears abnormal on a radiogram, without the involvement of the spinal cord and spinal nerves.^[rx] The risk of recurrence in those who have a first-degree relative (a parent or sibling) is 5–10 times greater compared to the general population
• Spina bifida occulta: failure of caudal neuropore to close. The spinal cord,  meninges, and overlying skin remain intact, with no herniation.
• Spina bifida cystica: meningocele (herniation of meninges only) and myelomeningocele (herniation of both meninges and neural tissue)

Main types of NTDs

Causes

Genetic and environmental factors exert a significant impact on the disruption of neurulation. Failure of neural folding or neuropores closure may be due to genetic changes, environmental factors, or lack of nutritional constituents. These insults cause neural tube defects in different ways, but the ultimate result is abnormal neurulation. The pathophysiology of NTDs based on the different etiologies is summarized here.

Folic Acid, Antagonists, and its Genetic Correlation

Following several research studies, researchers concluded that folic acid supplementation in a multivitamin regimen decreases the incidence rate of neural tube defects by 71%.[rx]

Folic acid has a major contribution to the pathophysiology of neural tube disorders. Folic acid helps synthesize deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) precursors. Folic acid is converted into tetrahydrofolate by dihydrofolate reductase enzymes. Methylation of folic acid is essential to take the folic acid functional.[rx] 5-methyl tetrahydrofolate (5-MTHF) is the active cofactor of enzymes involving one-carbon transfer reactions forming purine and pyrimidine. 5-MTHF is taken up by cells through folate receptors. A carrier protein and glutamates are added to form polyglutamate folates, which cannot cross the cell membranes and accumulate inside the cell.[rx] Hence, folic acid is directly associated with cell proliferation as in neurulation. The absence of folic acid halts neural tissue proliferation and migration during neurulation, leading to neural tube disorders.

In some cases, even pregnant women who receive sufficient folic supplementation acid give birth to a child with neural tube disorders. Research has shown that genetic alterations in folate metabolism, folate receptors, and transport proteins render these women susceptible. Neural folds express the folate receptors. Genetic defects in these receptors, particularly folate alpha and beta receptors, which take up folate derivatives inside neural cells required for replication, lead to failure of neurulation.[rx]

Meta-analysis performed to rule out the relation between MTHFR C677T polymorphism, and neural tube defects demonstrated that this mutation decreases the activity of enzymes required for folate metabolism, thus reducing the serum folate concentration.[rx] Folate antagonists such as phenytoin, valproic acid, and carbamazepine have a direct effect on NTDs by inhibiting the activity of folate.[rx] Methotrexate inhibits dihydrofolate reductase. The use of methotrexate increases the apoptosis of neural tissue contributing to NTDs.[rx]  Mutation in homeobox genes and fibroblast growth factor (FGF) dysfunction have some roles in the pathogenesis of NTDs.

Vitamin B12, Homocysteine, and Folate Receptor Autoantibodies

Vitamin B12 helps convert homocysteine formed from folate metabolism into methionines with the help of methionine synthase o reduce the toxicity of homocysteine. The deficiency of vitamin B12 increases the homocysteine level in the serum. One hypothesis suggests that high homocysteine level causes posttranslational modification of folate receptors (homocysteinylation) which forms folate receptors into a self-antigen. Antibodies are formed against these auto-antigens, and therefore the activity of folates declines.[rx]

Diabetes and Immune Modulation

Gestational diabetes increases the Central nervous system malformations by 2-10 folds. Exposure to elevated glucose is teratogenic to embryos less than seven weeks with the undeveloped pancreas. A study conducted on Xenopus frogs concluded the necessity of chemokines and complement factors in the central nervous system (CNS) development. So absence or reduced level of C3a and C5a has some roles in NTDs.[rx]

Diagnosis

Women of childbearing age may present with a history of low socioeconomic status, lack of folic acid supplementation during pregnancy, family history, weakness, fatigue, dyspnea due to anemia, diabetes, and drug intake for epilepsy. Diagnosis is usually made both prenatal and postnatal. Prenatal diagnosis is made through ultrasound screening. Sometimes it may be discovered in older children or even adults.[rx] Anencephaly is more lethal and so diagnosed easily antenatally. Urinary symptoms, neurological weakness, and cardiovascular complaints are often associated with NTDs.

Physical examination of NTDs varies according to the size and type of defects. Open NTDs are easily visible, whereas it may take effort to detect closed types. The birth weight of the child may be low. About one-third of the cases are associated with other congenital anomalies present with cleft palate, undescended testis, omphalocele, and talipes.[rx] Increased circumference of the head complicated by hydrocephalus. Closed spinal defects are associated with lipomyelocele and lipomeningomyelocele. Dorsal enteric fistula, anal imperforation, cardiac and renal abnormalities in abnormal notochord formation, a tuft of hair, and scoliosis in case of diastematomyelia, polydactyly associated with encephalocele are the additional features that may be present in rare conditions.[rx] Myelomeningocele is often a sac-like structure with CSF fluid leak. Late ambulation and cognitive impairment are present. The mother may be pale and anemic.

Lab test

• Ultrasound – It is the investigation of choice in prenatal screening. Ultrasound localizes the exact size and site of neural tube defects and vertebrae.[rx] Accurate diagnosis of anomalies with the help of ultrasound depends upon the gestational age of the fetus and careful evaluation of anomalies.
• Serum Alpha-fetoprotein – Alpha-fetoprotein is a globulin protein formed by the fetal yolk sac, liver, and gastrointestinal tract. Initially, its concentration is greater in amniotic fluid and fetal plasma as compared to maternal serum. But as gestation advances, due to increased permeability of the placenta, alfa-fetoprotein crosses the fetal-placental barrier so that maternal serum alfa-fetoprotein level rises and amniotic fluid and fetal plasma decreases. A high level of alfa-fetoprotein indicates neural tube defects. In addition, the acetylcholinesterase level is estimated in the case of abnormally high levels of alpha-fetoprotein. Though serum alpha-protein level has an important role in screening neural tube defects, it is not a cost-effective approach.[rx]
• Magnetic Resonance Imaging (MRI) – MRI is performed in cases of uncertain ultrasound description to evaluate the anomalies more accurately. Although MRI has a diagnostic role in cases of neural tube defects, some studies in chick embryos showed that MRI exposure increases the incidence of neural tube disorders.[rx]
• Chromosomal Microarray – As it is clear that neural tube disorders can contribute to genetic abnormalities, genetic testing estimates the association between genetic mutation and neural tube defects.[rx]
• Associated Anomalies – In many cases, neural tube defects are associated with other anomalies such as cardiovascular, cleft palate, urinary tract infections, coloboma, etc.
• Maternal Serum Folic Acid Level – Maternal serum folic acid level before or during conception helps to rule out the causative factors of NTDs.[rx]

Treatment

• Folic Acid Supplementation – Many studies suggested that periconceptional folic acid supplementation with the fortification of a diet rich in folic acid has significant results (50% to 70%) in preventing neural tube disorders. The recommended dose of folic acid for all women desiring pregnancy is 0.4 to 0.8 mg per day.[rx] However, women who already have had a child with NTD or positive family history should take 4 mg of folic acid daily one month before the conception through the first three months of pregnancy to prevent the recurrence. Some studies suggest that it takes approximately 20 weeks to achieve a normal red-blood-cell level of folic acid to prevent neural tube defects.[rx] So women should receive folic acid 5 to 6 months before conception.
• Fetal and Postnatal Surgery for Myelomeningocele – Surgical repair of myelomeningocele in fetus stops leakage of spinal fluid and therefore arrests the herniation of cerebellum, preventing hydrocephalus formation. Postnatal surgical closure of spina bifida should occur within 72 hours. Randomized control trials in the United States proposed that improved ambulation and cognitive behavior are more with prenatal than postnatal surgery.[rx] Recently published data indicate that prenatal repair may improve bladder function with less trabeculation of the bladder than conventional postnatal surgery.[rx][rx]
• Ventriculoperitoneal Shunt – Hydrocephalus is treated by a ventriculoperitoneal shunt, draining the CSF from the ventricles to the peritoneal cavity.
• Antipyretics – The use of antipyretics in hyperthermia reduces the chances of NTDs.[rx]
• Prenatal counseling – Once the prenatal ultrasound and other investigations confirm the diagnosis of NTD, the mother and family members should receive counsel regarding the management, possible prognosis, complications, and referral to other specialties for a comprehensive approach to the disease.
• Control of Gestational Diabetes – A pregnant mother with diabetes has an increased chance of a child with NTDs. Therefore, control of gestational diabetes helps to prevent and reduce the incidence of NTDs.
• Postnatal Assessment and Management – In the absence of prenatal screening, children with NTDs require immediate assessment after birth about the site of any defects, size, leakage of cerebrospinal fluid, and any infections, which should be managed accordingly. Ensure aseptic measures during the assessment. The use of non-latex gloves reduces the risk of latex sensitization. Broad-spectrum antibiotics coverage to prevent infections, sterile and saline-soaked dressing, the neurological assessment helps in a wide range to facilitate postnatal life. The surgical management of closed neural tube defects is challenging and complex. Practitioners must be familiar with the underlying embryology associated with the specific defect and the contemporary surgical management to reduce the risk of CSF fistula formation or neurologic compromise, which leads to high morbidity. Neural tube disorders are classified based on-site and covering and its contents. So they have to be differentiated from each other at first for proper approach and interventions. They may be open or closed, spinal cord originated, or brain originated. Open spinal dysraphisms are myelomeningocele, hemimyelocele, lipomyelomeningocele, meningocele, and lipomyelocele are the few closed types. Anencephaly is also possible.[rx]
• Iniencephaly – It is the rare and lethal spondylocostal dysplasia associated with spina bifida, heart defects, cleft palate, and renal abnormalities.[rx] The involvement of the thoracic vertebra and the absence of ribs with kyphosis helps to differentiate this disease from neural tube defects through such clinical presentation that may be minimally present or absent, making it difficult for diagnose.
• Meckel-Gruber Syndrome – Meckel-Gruber syndrome is an autosomal recessive disease comprised of a group of disorders involving the malfunction of cilia. Neural tube defects, mostly occipital encephalocele, are part of this syndrome. Besides encephalocele, this syndrome consists of other systems that have cilia as the main functioning role, such as the respiratory tract, oviduct or efferent ducts, renal tubules, brain ventricles, etc. The presence of respiratory disease, infertility, and polycystic kidney disease hydrocephalus is important to rule out isolated neural tube disorders from Meckel-Gruber syndrome.[rx]
• Tethered Cord Syndrome – Adhesions cause an abnormal stretching of spinal cords, mostly due to lipoma, dermoid cysts, rumors, etc.
• Viral and Neonatal Meningitis – The primary causative organisms of neonatal meningitis are group B streptococcus and enterovirus for viral meningitis. Meningitis cause premature births along with signs and symptoms such as neck rigidity, and fever that confuses meningitis in patients with neural tube defects.
• Lipomyelomeningocele – It is an intradural lipoma attached to surrounding soft tissue leading to the tethered spinal cord deteriorating the neurological functions.[rx] The formation of humps mainly in the cervicothoracic region confuses neural tube defects.
• Myelocystocele – Myelocystocele is a closed neural tube defect that resembles myelomeningocele, especially when complicated by hydrocele.[rx]
• Neurenteric Cyst – It is formed due to an abnormal connection between the ectoderm and endoderm. They are common in neural crest cells found in the brain and spinal cord in rare cases mimicking neural tube defects.[rx]
• Persistence of Terminal Ventricle – It is a rare case present as a cavity in conus medullaris that can be visualized in radiological investigations.[rx]

Complications

• Stillbirths and Abortion – Stillbirths and preterm labor leading to abortion is the serious complication NTDs.[rx]
• Polyhydramnios – It is typically associated with anencephaly because there is no mechanism for the swallowing reflex so that amniotic fluid remains accumulated in the amniotic sac. This condition is obvious; patients with neural tube disorders have a learning disability as there has been the arrest of the development of neural tissue. According to the conducted study, it is estimated that around 27% of pregnancies with anencephaly developed polyhydramnios few require amniodrainage in the third trimester.[rx] Polyhydramnios usually develops in second and third trimesters in about 50% of patients.
• Arnold-Chiari Malformation – It is defined as the downward displacement (herniation) of part of the cerebellum into the foramen magnum because of the tethering of the spinal cord in the vertebral column due to its abnormal development (spina bifida).[rx]
• Hydrocephalus – Brain malformation has a direct impact on the development of hydrocephalus. Encephalocele is associated with the communicating type of hydrocephalus.
• Meningitis – Continuous leakage of cerebrospinal fluid paves the easy access to meninges for normal naso-oropharynx such as streptococci, and enterococci. Children with NTDs are susceptible to meningitis.[rx]
• Cognitive disability –  Normal CSF pressure, osmolarity, and constituents of CSF are required for the proper development of the brain, mainly the cerebral cortex. Patients with NTDs have less cortical development even with the normal head size due to the free flow of CSF down through spina bifida. Neural cell proliferation and migration are deranged by abnormal CSF physiology.[rx]
• Spinal fistula – Spinal fistula formation and a continuous discharge of CSF are common in some cases.
• Complications due to fetal surgery – Preterm delivery, obstetric complications, pulmonary edema percutaneous fetoscopic vs. open repair: preterm birth and placental rupture are more common in percutaneous fetoscopic surgery, whereas the rate of uterine dehiscence is more in open surgery.[rx]

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